Reproductive, Developmental and General Toxicity Study of 3'-Azido-3'-Deoxythymidine (CAS No. 30516-87-1) and 2',3'-Dideoxycytidine (CAS No. 7481-89-2) Combinations in CD-1 Mice
Report Date: June 14, 1993
Abstract
The toxicity of AZT/ddC combination therapy was assessed in Swiss mice . Oral doses of AZT (100, 200, 400 mg/kg/day) were given alone or in combination with ddC (200, 500, 1000 mg/kg/day) . Male mice (10/group) were dosed from study day 5 until the day prior to sacrifice on Study Day 25 or 26. Prior to dosing, (study days 0-4) the male mice were cohabited with female mice (20/group). The sperm-positive female mice were dosed on days 6 through 15 of gestation and sacrificed on scheduled Day 4 of lactation. A second group of female mice (20/group) were dosed from study day 0 throughout mating on study days 9 to 13 until sacrifice on day 18 of gestation. Adult mice were evaluated for clinical signs, body weight, and hematologic parameters, and offspring were evaluated for viability, external anomalies, and weight.
The primary toxicity observed in male mice administered AZT alone or in combination with three dosages of ddC was hematologic toxicity. AZT alone induced dose-related leukopenia, and thrombocytosis. ddC alone induced marginal anemia and thrombocytosis combination, AZT and ddC produced additive, and/or synergistic effects on the hematologic toxicities induced by each agent alone. This was most notable at the high dose of ddC and ddC in combination also caused a statistically significant interaction effect in epididymal sperm motility; however, neither AZT nor ddC alone had a significant effect.
In female mice both hematologic and reproductive/developmental toxicities were observed. In the females (a), AZT alone induced marginal anemia and thrombocytosis. ddC alone induced anemia, leukopenia, and thrombocytosis at the high dose. In the females (b), AZT alone induced a marginal anemia and ddC alone induced thrombocytosis. In combination, AZT and ddC produced additive and/or synergistic effects on hematologic toxicities in both the females (a) and females (b), with anemia, reticulocytopenia, leukopenia, and thrombocytosis/thrombolcytopenia observed.
In regard to reproductive/developmental toxicity, the 100 and 200 mg/kg/day dosages of AZT alone produced minimal, if any, maternal toxicity. The toxicity that was produced (decreased body weight and body weight gains) was probably related more to reduced litter sizes, increased resorptions, and reduced fetal weights that occurred in these dosage groups, as the average corrected body weights were not reduced in these two groups. The 400 mg/kg/day dosage of AZT produced both maternal and developmental toxicity.
ddC alone administered at dosages of 200 and 500 mg/kg/day produced no maternal toxicity. Dosages of 1000 mg/kg/day alone were clearly maternally toxic.
Both ddC and AZT appeared more toxic to the developing conceptus and pup than to the adult animal. Dosages of 100, 200, and 400 mg/kg/day of AZT alone and 500 and 1000 mg/kg/day of ddC alone produced developmental toxicity.
Administered in combination, AZT and ddC produced increased maternal and developmental toxicity. These increases were both additive (more severe toxicity was produced by the combination AZT and ddC then was produced by each test article alone) and synergistic (dosages of AZT or ddC when administered alone produced no toxicity, when administered in combination produced toxicity).
Overall, the results suggest that coadministration of AZT and ddC results in additive and/or synergistic activity for hematologic and reproductive/ developmental toxicity.